Radioimmunotherapy of cancer
Monoclonal antibodies or pretargeting strategies can be used to specifically deliver radionuclides to the tumor, while sparing normal tissue. Two examples of clinical studies carried out at our department:
For renal cell carcinoma, the radiolabeled chimeric monoclonal antibody girentuximab has been extensively studied. Girentuximab specifically targets carbonic anhydrase IX (CAIX), a tumor-associated antigen ubiquitously expressed in primary ccRCC and its metastases. Because of the specific targeting of girentuximab to CAIX-expressing lesions, this antibody is a potent carrier for tumor-targeted delivery of β-emitting radionuclides. In a phase 1 clinical trial, lutetium 177 (177Lu)–girentuximab RIT proved to be safe and well tolerated. Moreover, 74% of the patients with advanced ccRCC demonstrated stable disease (SD). In a subsequent nonrandomized single-arm phase 2 study (n=14), eight patients (57%) had SD and one (7%) had a partial regression. Treatment was generally well tolerated but resulted in grade 3–4 myelotoxicity in most patients.
Monoclonal antibodies are limited by their slow blood clearance. Pretargeting with a non-radiolabelle bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabeled hapten peptide improves tumour localization and lowers the radiation exposure to normal tissue. We have performed a pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabeled hapten-peptide, IMP288, to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). This phase I study demonstrated for the first time that pretargeting with bsMAb TF2 and radiolabeled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.
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Publications
- R. Schoffelen, W. der Woliner-van Weg, E. Visser, D. Goldenberg, R. Sharkey, W. McBride, C. Chang, E. Rossi, W. van der Graaf, W. Oyen and O. Boerman. "Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer", 2014. Abstract/PDF DOI PMID
- R. Schoffelen, O. Boerman, D. Goldenberg, R. Sharkey, C. van Herpen, G. Franssen, W. McBride, C. Chang, E. Rossi, W. van der Graaf and W. Oyen. "Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results", 2013. Abstract/PDF DOI PMID
- A. Stillebroer, O. Boerman, I. Desar, M. Boers-Sonderen, C. van Herpen, J. Langenhuijsen, P. Smith-Jones, E. Oosterwijk, W. Oyen and P. Mulders. "Phase 1 radioimmunotherapy study with lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma", 2013. Abstract/PDF DOI PMID
- A. Stillebroer, C. Zegers, O. Boerman, E. Oosterwijk, P. Mulders, J. O'Donoghue, E. Visser and W. Oyen. "Dosimetric analysis of 177Lu-cG250 radioimmunotherapy in renal cell carcinoma patients: correlation with myelotoxicity and pretherapeutic absorbed dose predictions based on 111In-cG250 imaging", 2012. Abstract/PDF DOI PMID
- A. Brouwers, W. Buijs, P. Mulders, P. de Mulder, W. van den Broek, C. Mala, E. Oosterwijk, O. Boerman, F. Corstens and W. Oyen. "Radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell cancer: dosimetric analysis and immunologic response", 2005. Abstract DOI PMID
- A. Brouwers, P. Mulders, P. de Mulder, W. van den Broek, W. Buijs, C. Mala, F. Joosten, E. Oosterwijk, O. Boerman, F. Corstens and W. Oyen. "Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma", 2005. Abstract DOI PMID